ABSTRACT Venous thromboembolism (VTE) remains a significant healthcare problem with over a 100,000 deaths per year in the United States and still remains a diagnostic challenge. Even today, in the era of targeted therapeutics for cancer and immunologic therapies for autoimmune diseases, there exists no direct method to image intravascular thrombi. Currently available imaging methods to diagnose VTE rely on indirect assessments to detect thrombi, such as filling defects on CT angiography or lack of venous compressibility with ultrasound and suffer from diagnostic errors leading to high false positive and false negative rates that subject patients to the risk of death from pulmonary embolus, or major bleeding from unnecessary anticoagulation. Our long-term research objective of this translational study is to establish a novel thrombus body scan (TBS) using a new fibrin-specific probe for positron emission tomography (PET) imaging to overcome the limitations of indirect VTE diagnosis, and, with one single test, provide a total-body assessment of fresh intravascular clot. This proposal aims to generate strong evidence for VTE diagnosis using the thrombus body scan or TBS from an initial small translational study that will justify larger clinical study to obtain clinical approval for the TBS. We hypothesize that TBS using our new PET fibrin probe that specifically binds to fresh polymerized fibrin clot (< 1 week old), can directly detect thrombus anywhere in the body similar to 18F- FDG PET scans for cancer nodules, will have better diagnostic accuracy for deep venous thrombosis and pulmonary embolus (DVT-PE) compared to current imaging modalities, can quantify the total body burden of fresh clot and can be performed in patients with renal dysfunction. Before we can fully test this hypothesis in an appropriately-powered clinical study, we propose a proof-of-concept study in a smaller cohort of patients to test the following specific aims: SA-1: Compare PE diagnosed by the PET fibrin probe with conventional imaging (CT- or PA-angiogram). SA-2: Compare DVT diagnosed by the PET fibrin probe with conventional imaging (venous duplex ultrasound). SA-3: Assess the prevalence of upper extremity and pelvic clot in addition to PE-DVT and compare the extent of total body clot burden imaged with the PET fibrin probe to the plasma D-dimer level. Successful execution of this study will lay the groundwork for a clinical trial to compare the efficacy of a clot- specific imaging modality (thrombus body scan or TBS) that has the potential to be more accurate for the diagnosis of VTE, better able to establish the total clot burden in the body with a single test and more widely applicable to patients with renal failure and lung disease.